| Summary: | 博士 === 國立成功大學 === 基礎醫學研究所 === 93 === Learning and memory is the basis for the survival and development of creatures, however, aversive experience of fear leads to anxiety. With the changes of the society, anxious complications happen commonly in the modern life. Therefore, the problems of anxiety can be solved by an understanding of emotional fear in terms of its underlying cellular and molecular mechanisms.
NF-kB, originally identified as a regulator of immunoglobulin k light chain gene expression, is a DNA-binding factor that functions as a dimer. Recent studies indicate that NF-kB played an important role in the synaptic plasticity. Therefore, we used fear-potentiated startle paradigm to identify the role of NF-kB signaling pathway in memory formation. The results show that p50 and p65 subunits of NF-kB were selectively activated in the amygdala following fear conditioning through the signal-induced activation of PI-3 kinase, IKK and subsequent proteolytic degradation of IkB-a in the cytoplasm. This allows NF-kB to translocate into the nucleus where it binds to specific�nkB DNA consensus sequences in the enhancer region of�n�羠-responsive genes. Pharmacological blockade of NF-kB impairs fear memory in a dose-dependent manner. In in vitro slice preparation, bath application of kB decoy DNA attenuates tetanus-induced L-LTP in the amygdala. Therefore, a novel role of NF-kB in fear conditioning and synaptic plasticity has been demonstrated here.
CBP/p300 contains histone acetyltransferase that has been implicated in the regulation of gene expression. Recent studies show that the action of NF-kB is regulated by reversible acetylation. We found that the expression of acetyl-p65 subunit was selectively increased in the amygdala following fear conditioning through the increase associated with CBP (CREB binding protein). Pharmacological blockade of histone deacetylase further increase DNA binding activity of NF-kB and fear memory in a dose-dependent manner. In in vitro slice preparation, bath application of histone deacetylase inhibitor increases the degree of forskolin-induced L-LTP in the amygdala. Therefore, a novel role of NF-kB in fear conditioning and synaptic plasticity has been demonstrated. These results suggest that HDAC-mediated deacetylation functions as an intranuclear molecular switch culminating in the termination of NF-kB transcriptional response.
AMPA receptors mediate the majority of the fast excitatory synaptic transmission. One recently identified mechanism contributing to synaptic plasticity is the regulated trafficking of AMPA receptors in and out of synapses. Receptors with long cytoplasmic tails (GluR4/2 and GluR1/2) are driven into synapses in an activity-dependent manner. Our results show that synaptoneurosome membrane expression of GluR1 was selectively increased in the amygdala following fear conditioning through the signal-induced activation of PI-3 kinase, NMDA receptor and NF-kB. Pharmacological blockade of histone deacetylase further increases conditioning-induced membrane expression of GluR1 in NF-kB-dependent manner. Furthermore, fear training-induced increase in GluR1 was reversed when animal was exposed to the memory extinction protocol. The reversal of GluR1 increase was also blocked by D-APV and anisomycin treatment. The similar pattern of changes in GluR1 was observed in the amygdala slices after delivery of high-frequency stimulation (HFS) or HFS followed by low-frequency stimulation (LFS) that elicited long-term potentiation (LTP) and depotentiation respectively. These results suggest that long-term synaptic plasticity and memory formation are correlated with the changes in modification of GluR1 expression, and surface expression of GluR1 is a potential effector that contributes at least in part to the expression of fear memory.
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